The aims of this proposal are both biological and technical. The biological goals relate to detailed genomic analysis of the 20-30 cM regions surrounding the homeobox complex loci on human and mouse chromosomes 7/17 and 6/11. We believe the Hox-l and Hox-2 loci on human chromosomes 7 and 17 are parologous and represent an extensive duplication which occurred before the divergence of the human and mouse lineages 60-70 My ago. We further posit that many genes in the vicinity of the homeobox loci maybe functionally interrelated and that these domains may coordinate developmental and other biological processes. The technical aims of this project focus on the development of methods that will together speed up genomic analysis by a factor of five to ten fold. These will include (1) the design of new cloning vectors capable of cloning inserts of 160 bp in bacterial hosts and in the megabase range in yeast hosts, (2) the design and synthesis of chemical reagents which will permit the site specific scission of double stranded DNA, and (3) the development of integrated methods of high resolution physical and Mendelian gene mapping methods. In sum, we believe this integrated ensemble of projects will provide new insights into current biomedical problems of significance, and to contribute new methodologies which will substantially enhance our ability to analyze complex genomes, both in germs of speed and resolution.